Download The yin and the yang of p27Kip1 as a target... EDITORIAL B. Eymin, E. Brambilla

Copyright #ERS Journals Ltd 2004
European Respiratory Journal
ISSN 0903-1936
Eur Respir J 2004; 23: 663–664
DOI: 10.1183/09031936.04.00019504
Printed in UK – all rights reserved
EDITORIAL
The yin and the yang of p27Kip1 as a target for cancer therapy
B. Eymin, E. Brambilla
Schematically, human tumours arise because tumour cells
escape from extracellular signals that physiologically monitor
cellular proliferation, as well as cell death, and acquire
the property to grow continuously. During tumourigenesis,
many proteins that normally control the proper timing of
cell growth, e.g. the cyclins, or prevent the occurrence of
unappropriate apoptosis are abnormally expressed or activated,
and act as typical oncogenes leading to hyperproliferation
and/or protecting tumour cells from death. In contrast,
proteins that normally prevent, for example, damaged cells
to progress into the next phase of the cell cycle or act as
apoptosis inducers, if the damage can not be repaired, are
frequently inactivated in tumour cells and act as tumour
suppressor genes. Therefore, loss of tumour suppressor genes
associated with abnormal hyperactivity of oncogenes classically contribute to human carcinogenesis. However, affecting
a clear-cut function of tumour suppressor or oncogene
remains a subject of debate for certain proteins. The p27Kip1
is a member of the cyclin-dependent kinase inhibitory
proteins, which also include: p21WAF1, the target gene of
p53; p16INK4a, a member of the retinoblastoma (Rb)
pathway; and p57Kip2. In combination with p16INK4a, it
plays a major role in counteracting the activity of cyclins D1
and E on Rb phosphorylation and subsequent G1-S
transition. Therefore, it coordinates the activation of cyclin
E-cdk2 with accumulation of cyclin D-cdk4 and initiates the
timely exit of cells from the cell cycle in response to
antimitogenic signals. Alongside its classical antiproliferative
function, p27Kip1 can also promote or inhibit apoptosis
depending on the context [1, 2]. Based on these data, p27Kip1
presents most of the classical features of a tumour suppressive
protein that might be lost in proliferative tumour cells.
Unlike most of the tumour suppressor genes, where loss of
function responds to the classical "two-hit hypothesis" of
tumor suppression (Knudson law), p27Kip1 gene is not
deleted (there is neither loss of heterozygosity nor homozygous deletion), and does not suffer aberrant methylation of
its 59-end in tumours. Rather, in mouse models, p27Kip1 was
shown to be a dosage-dependent tumour suppressor, since
loss of a single allele of p27Kip1 increases the frequency and
decreases the latency of tumours to a level intermediate to
that seen in wild-type and null counterparts [3].
In human tumours, a direct correlation between p27Kip1
protein levels and survival chances was first noted in colon
cancer and later in cancers of the breast, prostate, bladder,
ovary, lung and other tissues; SINGERLAN and PAGANO [4]
give a concise review regarding p27Kip1 and these cancers.
The evidence that reduced p27Kip1 may contribute to tumour
development by either increasing the proliferation of cells or
decreasing their apoptosis might explain why the loss of
p27Kip1 is a common marker among many different tumour
Correspondence: B. Eymin, INSERM U578 Lung Research Group,
Institute Albert Bonniot, Domaine de la Merci 38706, La Tronche,
Cedex, France. Fax: 33 476549509. E-mail: [email protected]
types. It also suggests that p27Kip1 maybe a valuable target
for both stratifying patient risk and, perhaps, selecting treatment. However, observations that some human tumours
exhibit high levels of p27Kip1 makes this scheme more
complex. For example, in aggressive small cell lung cancer,
p27Kip1 overexpression has been suggested to protect cells
from apoptosis in unfavourable microenvironments [5]. In
addition, p27Kip1 might affect the efficacy of chemotherapies,
as these treatments work better in proliferating rather than in
growth-arrested cells. Therefore, it is necessary to keep in
mind that modulating p27Kip1 levels can have unforeseen
consequences on therapy, depending on the cell type and the
contextual clues.
In this issue, ISHII et al. [6] have studied the consequences of
p27Kip1 overexpression or downregulation in human lung
adenocarcinoma. The authors first show that overexpression
of p27Kip1 inhibits cell growth and rescues cells from death
instead of inducing apoptosis. More interestingly, using short
interfering (si)RNA technology, they demonstrate that neutralisation of endogenous p27Kip1 induces cell death of several
nonsmall cell lung cancer cell lines without affecting their cell
cycle status. Finally, after analysis of p27Kip1 subcellular
localisation and phosphorylation, the authors describe the
predominant cytoplasmic accumulation of endogenous p27Kip1
in these tumour cells, which might preclude it from regulating
the G1-S transition. p27Kip1 activity appears to be directly
targeted by its mislocalisation to the cytoplasm in colon or
ovarian tumours [7, 8]. In addition, the cytoplasmic p27Kip1
seems to correlate with poor long-term survival and tumour
grades in breast carcinoma [9]. Mislocalisation effectively
inactivates the p27Kip1 inhibitory activity, as cytoplasmic
p27Kip1 is partitioned from its nuclear cyclin-cdk targets.
However, as suggested by ISHII et al. [6], such cytoplasmic
localisation of p27Kip1 could also contribute to its antiapoptotic functions. Therefore, before considering therapies,
it is necessary to predict how cells in a particular tumour will
respond to the accumulation or neutralisation of p27Kip1. In
this context, the study by ISHII et al. [6] suggests that targeting
p27Kip1 in nonsmall cell lung cancer could inhibit their
growth by reducing cell viability. In contrast, in other tumour
types, it will be the restoration of p27Kip1 that will prevent
tumour growth, either by inhibiting cellular proliferation or
inducing apoptosis. Therefore, dependent upon the cancer
type, the goal of therapy targeting p27Kip1 will tend to either
neutralise or reintroduce it. It is the reason why comprehensive understanding of p27Kip1 biology would facilitate development of such therapeutic responses in human cancer. Hence,
it would be too simplistic to ascribe p27Kip1 only as a tumour
suppressive protein since its anti-apoptotic function might also
predict an "oncogenic" role. As a typical example of this "gain
of function" are the highly agressive small cell lung cancer,
which carry elevated levels of nuclear p27Kip1. Obviously,
more work needs to be performed so as to decipher the real
contribution of p27Kip1 in human lung-tumour growth.
In conclusion, it is now well established that the biological effects of numerous proteins might be quite different,
664
B. EYMIN, E. BRAMBILLA
sometimes even opposite, depending on the cellular model,
the context and their subcellular localisation. Therefore, before
designing general therapies against cancer, it is necessary to
study, very carefully, the specific proteins involved in each
carcinogenetic process, as well as to investigate the molecular
mechanisms by which the loss or hyperactivity of such
proteins contribute to the carcinogenesis. Finally, it is also of
great importance to think about the fact that modulating the
levels of proteins, which control essential processes, e.g.
cellular proliferation and apoptosis, might interfere with the
response of tumour cells to chemotherapeutic treatments as
well as having unpredicted consequences.
3.
4.
5.
6.
7.
References
1.
2.
Katayose Y, Kim M, Rakkar AN, Li Z, Cowen KH, Seth P.
Promoting apoptosis: a novel activity associated with the
cyclin-dependent kinase inhibitor p27. Cancer Res 1997; 57:
5441–5445.
Eymin B, Haugg M, Droin N, Sordet O, Dimanche-Boitrel MT,
Solary E. p27Kip1 induces drug resistance by preventing
apoptosis upstream of cytochrome c release and procaspase3 activation in leukemic cells. Oncogene 1999; 18: 1411–1418.
8.
9.
Fero ML, Rivkin M, Tasch M, et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis
and female sterility in p27Kip1-deficient mice. Cell 1996; 85:
733–744.
Slingerland J, Pagano M. Regulation of the cdk inhibitor
p27 and its deregulation in cancer. J Cell Physiol 2000; 183:
10–17.
Masuda A, Osada H, Yatabe Y, et al. Protective function
of p27(KIP1) against apoptosis in small cell lung cancer cells
in unfavorable microenvironments. Am J Pathol 2001; 158:
87–96.
Ishii T, Fujishiro M, Masuda M, et al. Effects of p27Kip1 on
cell cycle status and viability in A549 lung adenocarcinoma
cells. Eur Resp J 2004; 23: 665–670.
Ciaprrone M, Yamamoto H, Yao Y, et al. Localization and
expression of p27Kip1 in multistage colorectal carcinogenesis. Cancer Res 1998; 58: 114–122.
Hurteau JA, Allison BM, Brutkiewicz SA, et al. Expression
and subcellular localization of the cyclin-dependent kinase
inhibitor p27(KIP1) in epithelial ovarian cancer. Gynecol
Oncol 2001; 83: 292–298.
Viglietto G, Motti ML, Bruni P, et al. Cytoplasmic
relocalization and inhibition of the cyclin-dependent kinase
inhibitor p27Kip1 by PKB/Akt-mediated phosphorylation in
breast cancer. Nat Med 2002; 8: 1136–1144.